Among the list of abnormalities that have been described in non- neural cells from patients with Alzheimer's disease, abnormal calcium homeostasis in lymphocytes and cultured fibroblasts is of particular interest. Altered calcium homeostasis has also been reported in Alzheimer neurones and can be linked by plausible mechanisms to their premature degeneration. The proposed studies will test the relationship of the alterations in calcium homeostasis to a well-characterized, calcium-dependent physiological cascade of events which appears to be impaired in Alzheimer's disease - namely, receptor-activated lymphocyte proliferation. The steps in this cascade will be compared in lymphocytes after stimulation with mitogens, with a calcium ionophore or with a cholinergic agonist. Emphasis will be placed on early and on physiologically critical "trigger" steps. Any abnormalities detected in lymphocytes will promptly be tested for in cultured fibroblasts and lymphoblasts. The ability of aminopyridines and other agents which act on calcium metabolism to ameliorate deficiencies in these processes in Alzheimer lymphocytes, fibroblasts, and lymphoblasts will be tested, both because of the direct therapeutic implications and to further probe the molecular mechanisms involved. The aims are to elucidate cellular patho-physiology in Alzheimer's disease, to identify peripheral markers, which may help in stratifying patients biologically (eg "a blood test"), and to provide simple systems to screen putative therapeutic agents.